Chlorothienyl-imidazole propenones

ABSTRACT

Disclosed are compounds represented by the following general formula and its hydrochloride salts: ##STR1## wherein A 1  stands for a phenyl group, a halophenyl group, a thienyl group or a halothienyl group, and A 2  stands for a phenyl group or a halophenyl group. 
     These compounds can be obtained by reacting an imidazole compound of the following formula: ##STR2## with a benzaldehyde compound of the formula A 2  -CHO. These compounds are valuable as fungicidal agents.

BACKGROUND OF THE INVENTION

(1) Field of the Invention

The present invention relates to a novel imidazole compound and aprocess for the preparation thereof.

The compound of the present invention is valuable as an antimildewagent, an antifungal or the like.

(2) Description of the Prior Art

It is known that certain imidazole compounds have a fungicidal action.For example, Japanese Patent Publication No. 16479/68 discloses1-hydroxy-2-undecyl-3-methylimidazolium-p-toluene-sulfonate,1-benzyl-2-undecyl-3-methylimidazolium methyl-sulfate and1-dodecyl-2-ethyl-3-benzylimidazolium chloride as fungicidal agents.Furthermore, the specification of U.S. Pat. No. 4,577,032 discloses1-benzyldibromomethyl-2-methylimidazole. The compound of the presentinvention has a much broader antimicrobial spectrum than those of theseknown compounds.

SUMMARY OF THE INVENTION

In accordance with the present invention, there are provided animidazole compound represented by the following general formula:##STR3## wherein A₁ stands for a phenyl group, a halophenyl group, athienyl group or a halothienyl group, and

A₂ stands for a phenyl group or a halophenyl group, and an acid additionsalt thereof, especially a hydrochloride thereof.

This hydrochloride salt is represented by the following general formula:##STR4## wherein A₁ and A₂ are as defined above.

These compounds can be prepared by reacting an imidazole compoundrepresented by the following general formula: ##STR5## wherein A₁ is asdefined above, with a benzaldehyde compound represented by the followinggeneral formula:

    A.sub.2 --CHO                                              (4)

wherein A₂ is as defined above.

It is preferred that in the above formula (1), the group A₁ be a grouprepresented by the following formula: ##STR6## wherein R₁, R₂ and R₃each stand for a hydrogen atom or a halogen atom, or a group representedby the following formula: ##STR7## wherein R₁ stands for a hydrogen atomor a halogen atom.

It also is preferred that the group A₂ be a group represented by thefollowing formula: ##STR8## wherein R₁, R₂ and R₃ each stand for ahydrogen atom or a halogen atom.

DESCRIPTION OF THE INVENTION

The imidazole compound of the formula (3) used as the starting compoundin the present invention is obtained by reacting imidazole with abromoacetophenone compound in dimethylformamide as the solvent (see E.F. Godefroi, J. Med. Chem., 12, page 784 (1969)). The intended compoundof the present invention is obtained by adding an equimolar amount of abenzaldehyde compound of the formula (4) to this imidazole compound ofthe formula (3), heating the mixture in the presence of piperidine in asolvent such as anhydrous benzene at 60° to 80° C., removing the solventunder a reduced pressure, and separating and purifying the intendedcompound by silica gel column chromatography of the residue or by addinga solvent such as isopropyl ether to the residue to precipitate acrystal and performing recrystallization from a solvent such as ethylacetate, petroleum ether or acetonitrile.

The intended compound in the form of a hydrochloride salt can beobtained according to the same procedures as described above except thata hydrochloric acid-alcohol solution is added to the above-mentionedresidue.

Compounds of the present invention are characterized in that they are inthe form of white or yellow crsytals, neutral or weakly acidic, hardlysoluble in water and soluble in ethyl acetate, petroleum ether,acetonitrile, isopropanol and ethyl ether.

These compounds have relatively broad antimicrobial spectrum and arevaluable as fungicidal agents.

The present invention will now be described in detail with reference tothe following examples that by no means limit the scope of theinvention.

EXAMPLE 1 Preparation of1-phenyl-2-(1H-imidazolyl)-3-(2,4-dichlorophenyl)-2-propen-1-one

To a solution of 2.8 g of 2-(1H-imidazolyl)acetophenone and 2.7 g of2,4-dichlorobenzaldehyde in anhydrous benzene was added 0.5 ml ofpiperidine, and the mixture was refluxed for 5 hours by using aDean-Stark trap. The solvent was removed by distillation under a reducedpressure and the residue was washed with petroleum ether two times.Isopropyl ether was added to the residue to precipitate a crystal andthe crystal was recrystallized from acetonitrile to obtain 3.4 g of awhite crystal having a melting point of 125° to 126° C. From the resultsof the analysis, it was confirmed that the product was1-phenyl-2-(1H-imidazolyl)-3-(2,4-dichlorophenyl)-2-propen-1-one havingthe following structural formula, and the yield was 66%.

(Structural Formula) ##STR9##

(Analysis Results)

Elementary analysis (as C₁₈ H₁₂ N₂ OCl₂, %); Found values: C=62.87,H=3.17, N=7.87; Calculated values: C=62.99, H=3.52, N=8.16.

TLC (chloroform/methanol=10/1) Rf: 0.56.

Infrared absorption spectrum (cm⁻¹) 1675 (C=0).

Nuclear magnetic resonance spectroscopy (chloroform-d₁, ppm) 6.44-7.89(12H, m, aromatic, ═CH).

EXAMPLE 2 Preparation of1-(4-chlorophenyl)-2-(1H-imidazolyl)-3-(4-chlorophenyl)-2-propen-1-one

To a solution of 3.3 g of 2-(1H-imidazolyl)-4'-chloroacetophenone and2.7 g of p-chlorobenzaldehyde in anhydrous benzene was added 0.5 ml ofpiperidine, and the mixture was refluxed for 5 hours by using theDean-Stark trap. Then, the solvent was removed by distillation under areduced pressure, and the residue was washed with petroleum ether twotimes, dissolved in ethyl acetate and cooled by ice to precipitate acrystal. Recrystallization was carried out by using ethyl acetate toobtain 3.6 g of white crystal having a melting point of 129° to 130° C.From the results of the analysis, it was confirmed that the product was1-(4-chlorophenyl)-2-(1H-imidazolyl)-3-(4-chlorophenyl)-2-propen-1-onehaving the following structural formula, and the yield was 70%.

(Structural Formula) ##STR10##

(Analysis Results)

Elementary analysis (as C₁₈ H₁₂ N₂ OCl₂, %); Found values: C=63.05,H=3.38, N=7.98. Calculated values: C=62.99, H=3.52, N=8.16.

TLC (chloroform/methanol=10/1) Rf: 0.54.

Infrared absorption spectrum (cm⁻¹) 1655 (C=0).

Nuclear magnetic resonance spectroscopy (dimethylsulfoxide-d₆, ppm),6.96 (2H, d, 4- or 5-positions of imidazole), 7.20 (2H, dd, 2-positionof imidazole, ═CH), 7.57-7.83 (6H, m, aromatic), ##STR11##

EXAMPLE 3 Preparation of1-(4-chlorophenyl)-2-(1H-imidazolyl)-3-(2,4-dichlorophenyl)-2-propen-1-onehydrochloride

To a solution of 3.3 g of 2-(1H-imidazolyl)-4'-chloroacetophenone and2.7 g of 2,4-dichlorobenzaldehyde in anhydrous benzene was added 0.5 mlof piperidine, and the mixture was refluxed for 5 hours by using aDean-Stark trap. The solvent was removed by distillation under a reducedpressure and the residue was washed with petroleum ether two times. Ahydrochloric acid-ethanol solution was added to the residue to adjustthe pH value to 1, and the mixture was refluxed for 5 minutes, and thesolvent was removed by distillation under a reduced pressure and etherwas added to the residue to precipitate a crystal. Recrystallizationfrom isopropanol gave 3.8 g of a white crystal having a melting point of177° to 179° C. From the analysis results, it was found that the productwas1-(4-chlorophenyl)-2-(1H-imidazolyl)-3-(2,4-dichlorophenyl)-2-propen-1-onehydrochloride having the following structural formula, and the yield was61%.

(Structural Formula) ##STR12##

(Analysis Results)

Elementary analysis (as C₁₈ H₁₂ N₂ OCl₃.HCl, %); Found values: C=52.29,H=2.79, N=6.47. Calculated values: C=52.21, H=2.92, N=6.76.

TLC (chloroform/methanol=10/1) Rf: 0.55.

Infrared absorption spectrum (cm⁻¹) 1650 (C=0).

Nuclear magnetic resonance spectroscopy (methylsulfoxide-d₆, ppm),6.93-7.08 (2H, d, 4- or 5-positions of imidazole), 7.25-7.39 (2H, dd,2-position of imidazole, ═CH), 7.55-7.81 (5H, m, aromatic). ##STR13##

EXAMPLE 4 Preparation of1-(4-chlorophenyl)-2-(1H-imidazolyl)-3-(2,4-difluorophenyl)-2-propen-1-one

To a solution of 2.2 g of 2-(1H-imidazolyl)chloroacetophenone and 1.5 gof 2,4-difluorobenzaldehyde in 80 ml of anhydrous benzene was added 0.2ml of piperidine, and the mixture was refluxed for 5 hours by using aDean-stark trap. The solvent was removed by distillation under reducedpressure, and the residue was separated and purified by silica gelcolumn chromatography (ethyl acetate/n-hexane=2/1). Recrystallizationfrom ethyl acetate and n-hexane gave 1.1 g of a white crystal having amelting point of 105° to 106° C. From the analysis results, it was foundthat the product was1-(4-chlorophenyl)-2-(1H-imidazolyl)-3-(2,4-difluorophenyl)-2-propen-1-onehaving the following structural formula, and the yield was 32%.

(Structural Formula) ##STR14##

(Analysis Results)

Elementary analysis (as C₁₈ H₁₁ N₂ OF₂ Cl, %); Found values: C=62.44,H=3.37, N=8.09. Calculated values: C=62.71, H=3.22, N=8.13.

TLC Rf: 0.74 (ethyl acetate/n-hexane=2/1). Rf: 0.68(chloroform/methanol=10/1).

EXAMPLE 5 Preparation of1-(4-bromophenyl)-2-(1H-imidazolyl)-3-(2,4-dichloro-phenyl)-2-propen-1-onehydrochloride

To a solution of 2.7 g of 2-(1H-imidazolyl)-4-bromoacetophenone and 1.8g of 2,4-dichlorobenzaldehyde in 80 ml of anhydrous benzene was added0.2 ml of piperidine, and the mixture was refluxed for 7 hours by usinga Dean-Stark trap. The solvent was removed by distillation under areduced pressure and hydrochloric acid-methanol solution was added tothe residue to dissolve. The solvent was removed by distillation under areduced pressure and ether and ethyl acetate were added to the residueto effect crystallization. Recrystallization from ethanol gave 2.2 g ofa white crystal having a melting point of 196° to 198° C. From theanalysis results, it was found that the product was1-(4-bromophenyl)-2-(1H-imidazolyl)-3-(2,4-dichlorophenyl)-2-propen-1-onehydrochloride having the following structural formula, and the yield was47%.

(Structural Formula) ##STR15##

(Analysis Results)

Elementary analysis (as C₁₈ H₁₁ N₂ OCl₂ Br.HCl, %); Found values:C=46.85, H=2.59, N=5.84. Calculated values: C=47.15, H=2.63, N=6.11.

TLC Rf: 0.80 (ethyl acetate/acetone=5/1). Rf: 0.76(chloroform/methanol=10/1).

EXAMPLE 6 Preparation of1-(5-chlorothien-2-yl)-2-(1H-imidazolyl)-3-(2,4-dichlorophenyl)-2-propen-1-one

To a solution of 3.4 g of1-(5-chlorothien-2-yl)-2-(1H-imidazolyl)ethanone and 2.7 g of2,4-dichlorobenzaldehyde in 80 ml of anhydrous benzene was 0.2 ml ofpiperidine, and the mixture was refluxed for 7 hours by using Dean-Starktrap. The solvent was removed by distillation under a reduced pressureand the residue was separated and purified by silica gel chromatography(chloroform/methanol=20/1). Recrystallization from ethyl acetate andisopropyl ether gave 2.1 g of a white crystal having a melting point of110° to 111° C. From the analysis results, it was found that the productwas1-(5-chlorothien-2-yl)-2-(1H-imidazolyl)-3-(2,4-dichlorophenyl)-2-propen-1-onehaving the following structural formula, and the yield was 37%.

(Structural Formula) ##STR16##

(Analysis Results)

Elementary analysis (as C₁₆ H₉ N₂ OSCl₃, %); Found values: C=50.19,H=2.15, N=7.61. Calculated values: C=50.09, H=2.36, N=7.30.

TLC RF: 0.79 (ethyl acetate/acetone=5/1). Rf: 0.80(chloroform/methanol=10/1).

EXAMPLE 7 Preparation of1-(5-chlorothien-2-yl)-2-(1H-imidazolyl)-3-(4-chlorophenyl)-2-propen-1-one

To a solution of 3.4 g of1-(5-chlorothien-2-yl)-2-(1H-imidazolyl)ethanone and 2.1 g of4-chlorobenzaldehyde in 80 ml of anhydrous benzene was added 0.2 ml ofpiperidine, and the mixture was refluxed for 6 hours by using aDean-Stark trap. The solvent was removed by distillation under a reducedpressure and ethyl acetate and isopropyl ether were added to the residueto effect crystallization. Recrystallization from ethyl acetate gave 1.7g of a yellow crystal having a melting point of 137° to 138° C. From theanalysis results, it was found that the product was1-(5-chlorothien-2yl)-2-(1H-imidazolyl)-3-(4-chlorophenyl)-2-propen-1-onehaving the following structural formula, and the yield was 32%.

(Structural Formula) ##STR17##

(Analysis Results)

Elementary analysis (as C₁₆ H₁₀ N₂ OSCl₂, %); Found values: C=55.30,H=2.66, N=8.29. Calculated values: C=55.03, H=2.89, N=8.02.

TLC Rf: 0.80 (ethyl acetate/acetone=5/1). Rf: 0.79(chloroform/methanol=10/1).

EXAMPLES 8 THROUGH 30

Imidazole compounds represented by the following structural formula:##STR18## were reacted with benzaldehyde compound represented by thefollowing structural formula:

A₂ --CHO

in the same manner as described in the foregoing examples to preparecompounds represented by the following structural formula: ##STR19## orhydrochlorides thereof. The properties of these compounds were examined.The obtained results are shown in Table 1.

                                      TABLE 1                                     __________________________________________________________________________                            Elementary Analysis                                                                             Infrared                                                    Values (%)  Melting                                                                             Absorption                          Example                 (calculated values)                                                                       Point Spectrum                            No.  A.sub.1  A.sub.2    C    H   N (°C.)                                                                        (CO, cm.sup.-1)                     __________________________________________________________________________     8                                                                                  ##STR20##                                                                              ##STR21##                                                                              63.21 (62.99)                                                                     3.19 (3.52)                                                                        7.88 (8.16)                                                                      150-151                                                                             1650                                 9                                                                                  ##STR22##                                                                              ##STR23##                                                                              79.23 (78.81)                                                                     4.97 (5.14)                                                                       10.19 (10.21)                                                                     114.5-115.5                                                                         1645                                10                                                                                  ##STR24##                                                                              ##STR25##                                                                              70.15 (70.02)                                                                     4.13 (4.24)                                                                        9.09 (9.07)                                                                        110-111.5                                                                         1650                                11                                                                                  ##STR26##                                                                              ##STR27##                                                                              70.26  (70.02)                                                                    4.00 (4.24)                                                                        8.82 (9.07)                                                                      78-79 1650                                12                                                                                  ##STR28##                                                                              ##STR29##                                                                              70.12 (70.02)                                                                     4.01 (4.24)                                                                        9.01 (9.07)                                                                      145-146                                                                             1665                                13                                                                                  ##STR30##                                                                              ##STR31##                                                                              63.23 (62.99)                                                                     3.35 (3.52)                                                                        7.82 (8.16)                                                                      103-105                                                                             1665                                14                                                                                  ##STR32##                                                                              ##STR33##                                                                              62.92 (62.99)                                                                     3.26 (3.52)                                                                        8.10 (8.16)                                                                      128-129                                                                             1670                                15                                                                                  ##STR34##                                                                              ##STR35##                                                                              57.28 (57.25)                                                                     2.87 (2.94)                                                                        6.89 (7.42)                                                                      120.5-122                                                                           1675                                16                                                                                  ##STR36##                                                                              ##STR37##                                                                              70.30 (70.02)                                                                     4.11 (4.24)                                                                        9.04 (9.07)                                                                      153.5-155                                                                           1655                                17                                                                                  ##STR38##                                                                              ##STR39##                                                                              62.74 (62.99)                                                                     3.36 (3.52)                                                                        7.87 (8.16)                                                                      81-83 1660                                18                                                                                  ##STR40##                                                                              ##STR41##                                                                              52.30 (52.21)                                                                     3.23 (2.92)                                                                        6.24 (6.76)                                                                      175-177                                                                             1675                                19                                                                                  ##STR42##                                                                              ##STR43##                                                                              52.08 (52.21)                                                                     2.78 (2.92)                                                                        6.51 (6.76)                                                                      167-174                                                                             1670                                20                                                                                  ##STR44##                                                                              ##STR45##                                                                              53.03 (52.46)                                                                     2.61 (2.45)                                                                        6.94 (6.80)                                                                      133-135                                                                             1675                                21                                                                                  ##STR46##                                                                              ##STR47##                                                                              63.88 (64.10)                                                                      4.02 (3.88)                                                                       7.99 (8.31)                                                                      162-167                                                                             1655                                22                                                                                  ##STR48##                                                                              ##STR49##                                                                              56.02 (55.76)                                                                     3.30 (3.12)                                                                        7.01 (7.22)                                                                      135.5-136.5                                                                         1655                                23                                                                                  ##STR50##                                                                              ##STR51##                                                                              50.15 (50.03)                                                                     2.68 (2.80)                                                                        6.32 (6.48)                                                                      158-159                                                                             1650                                24                                                                                  ##STR52##                                                                              ##STR53##                                                                              55.90 (55.76)                                                                     3.05 (3.12)                                                                        6.71 (7.22)                                                                      151-152                                                                             1650                                25                                                                                  ##STR54##                                                                              ##STR55##                                                                              66.15 (66.16)                                                                     3.48 (3.70)                                                                        8.81 (8.57)                                                                      124-125                                                                             1655                                26                                                                                  ##STR56##                                                                              ##STR57##                                                                              50.25 (50.09)                                                                     2.04  (2.36)                                                                       6.93 (7.30)                                                                      111-113                                                                             1670                                27                                                                                  ##STR58##                                                                              ##STR59##                                                                              55.20 (55.03)                                                                     2.65 (2.89)                                                                        7.93 (8.02)                                                                      137-139                                                                             1675                                28                                                                                  ##STR60##                                                                              ##STR61##                                                                              55.04 (55.03)                                                                     2.80 (2.89)                                                                        7.87 (8.02)                                                                        117-118.5                                                                         1675                                29                                                                                  ##STR62##                                                                              ##STR63##                                                                              55.34 (54.79)                                                                     2.56 (2.59)                                                                        7.83 (7.99)                                                                      117-118                                                                             1670                                30                                                                                  ##STR64##                                                                              ##STR65##                                                                              58.53 (58.24)                                                                     3.20 (3.26)                                                                        7.48 (7.55)                                                                      144.5-145.5                                                                         1650                                __________________________________________________________________________

Note

The products obtained in Examples 18 and 19 are hydrochloride salts.

EXAMPLE 31

With respect to the compounds obtained in the foregoing examples, theminimum growth inhibiting concentrations to pathogenic bacteria weremeasured. The obtained results are shown in Table 2. The unit of eachvalue in Table 2 is μg/ml. The used phthogenic bacteria were Candidaalbicans, Trichophyton rubrum, Trichophyton mentagrophytes, Trichophytontonsurans and Microsporum gypseum. Culturing was conducted inSabouraud's agar culture medium at 25° C. The growth of the bacteriumwas checked at intervals of 24 hours after inoculation. The minimumconcentration at which no colony was measured as the minimum inhibitoryconcentration after the passage of 7 days.

                                      TABLE 2                                     __________________________________________________________________________    Compound of                                                                   Present                                                                              Candida                                                                            Trichophyton                                                                         Trichophyton                                                                          Trichophyton                                                                         Microsporum                                 Invention                                                                            albicans                                                                           rubrum mentagrophytes                                                                        tonsurans                                                                            gypseum                                     __________________________________________________________________________    Example 1                                                                            <10  <2.5   <5      <2.5   <2.5                                        Example 2                                                                            <10  <1.25  <2.5    <2.5   <2.5                                        Example 3                                                                            <6.25                                                                              <1.25  <1.25   <1.25  <1.25                                       Example 4                                                                            <25  <3.125 <6.25   <0.782 <6.25                                       Example 5                                                                            <12.5                                                                              <3.125 <6.25   <0.782 <25                                         Example 6                                                                            50   <1.563 <25     <1.563 50                                          Example 7                                                                            25   <1.563 <1.563  <0.782 <6.25                                       Example 8                                                                            <25  <2.5   <5      <5     <2.5                                        Example 9                                                                            20   <10    <20     <20    20                                          Example 10                                                                           20   <5     <10     <10    <5                                          Example 11                                                                           20   <5     <10     <5     <5                                          Example 14                                                                           <50  <25    <50     <25    <25                                         Example 15                                                                           20   <20    20      <20    <20                                         Example 16                                                                           20   <5     <20     < 5    <10                                         Example 18                                                                           20   <20    20      <20    20                                          Example 21                                                                           50   <3.125 <12.5   <2.5   <3.125                                      Example 22                                                                           50   <2.5   <25     <6.25  <3.125                                      Example 23                                                                           <25  <12.5  <12.5   <3.125 <3.125                                      Example 24                                                                           <6.25                                                                              <1.56  <12.5   <0.391 <12.5                                       Example 25                                                                           50   <6.25  <12.5   <3.125 <50                                         Example 26                                                                           <25  <6.25  25      <6.25  <25                                         Example 27                                                                           25   <3.125 <3.125  <1.56  <12.5                                       Example 28                                                                           25   <12.5  25      <12.5  25                                          Example 29                                                                           <25  <12.5  <25     <3.125 <6.25                                       Example 30                                                                           <25  <12.5  <12.5   <3.125 <25                                         __________________________________________________________________________

We claim: 1.1-(5-Chlorothien-2-yl)-2-(1H-imidazolyl)-3-(2,4-dichlorophenyl)-2-propen-1-one.2.1-(5-Chlorothien-2-yl)-2-(1H-imidazolyl)-3-(4-chlorophenyl)-2-propen-1-one.